Electroacupuncture alleviates endometriosis by suppressing ferroptosis in murine ectopic and eutopic endometria via the Nrf2 pathway.

RESEARCH QUESTION: Does peritoneal iron overload drive fibrosis in endometriosis through Nrf2 pathway dysfunction and the resulting ferroptosis, and can electroacupuncture intervene in this process?

DESIGN

An endometriosis mouse model was established by intraperitoneal injection of syngeneic uterine fragments combined with periodic injection of whole blood, and subjected to electroacupuncture intervention. Fibrosis, ferroptosis-related markers, Nrf2/Keap1 pathway activity, the peritoneal microenvironment and systemic pathological indicators were systematically assessed using histological staining, molecular biology techniques and biochemical analyses.

RESULTS

Eutopic uterus and ectopic lesions in mice with endometriosis had significant fibrosis (P < 0.01) accompanied by pronounced ferroptosis (P < 0.01). Mechanistically, the Nrf2 pathway was functionally inactivated in these tissues, with impaired nuclear translocation (P < 0.01). Notably, in the eutopic uterus, this inhibition occurred independently of its classical regulatory protein Keap1, suggesting alternative regulatory mechanisms for Nrf2. Electroacupuncture treatment effectively suppressed lesion growth (P < 0.05) alleviated fibrosis (P < 0.01) and ferroptosis (P < 0.01), and also specifically reversed the impairment of Nrf2 nuclear translocation (P < 0.01) and improved systemic inflammation and endocrine disturbances.

CONCLUSIONS

To our knowledge, this study is the first to systematically demonstrate the pivotal role of the 'Nrf2 pathway inactivation‒ferroptosis‒fibrosis' axis in endometriosis, particularly in the eutopic uterus. Our findings provide a novel paradigm for understanding the pathological mechanisms of endometriosis and confirms that electroacupuncture exerts therapeutic effects by targeting this pathway, offering a solid experimental foundation for its clinical application.